Leptin is a protein produced by adipose tissue and hypothesized to be a circulating lipostatic factor (82). Our preliminary data shows that leptin infusion into normal mice inhibits insulin release in response to a glucose challenge, induces insulin resistance in adipocytes, but promotes insulin-stimulated glycogen synthesis in muscle. An impaired acute insulin release in response to glucose is a risk factor for development of non-insulin dependent diabetes (NIDDM) (25) and increased insulin-stimulated glycogen synthesis in muscle is characteristic of the early metabolic changes observed during the development of insulin resistance in high-fat fed rats (48). We hypothesize that leptin mediates development of an impaired glucose tolerance that precedes early NIDDM by suppressing glucose stimulated insulin release and modifying insulin-stimulated glucose utilization in a tissue and pathway specific manner. Experiments described in Specific Aim 1 will examine the effects of leptin infusion on glucose and fatty acid metabolism of the three major insulin-responsive tissues in lean mice and will determine whether the effects on insulin responsiveness are mediated by the long-form leptin receptor, OB-Rb. Experiments in Specific Aim 2 will investigate the role of leptin in modifying insulin signaling to determine whether leptin changes tissue insulin receptor number, glucose transporter number or translocation, and insulin receptor tyrosine kinase activity. These processes represent the first stage of the insulin signaling cascade and the results of these experiments will determine how leptin modifies the initial stages of insulin signaling to change peripheral tissue glucose utilization. The studies described in this proposal will provide the information required to understand how leptin treatment modifies insulin responsiveness in peripheral tissues and the mechanisms by which this is achieved. It is essential to elucidate this aspect of leptin activity as it may account for the increased risk of development of glucose intolerance that is associated with obesity.